IgA nephropathy (IgAN) is a form of glomerulonephritis which involves mesangial deposition of immune complexes containing IgA, IgG and complement. Evidence suggests that patients with IgAN have abnormal immunoregulation of systemic IgA production. There appears to be a familial predisposition to the development of IgAN. Patients' relatives may, therefore, also have abnormal IgA immunoregulation. Animal models of IgA nephropathy indicate that the quality and quantity of an IgA response influence its nephritogenic potential. This proposal would test the hypothesis that individuals inherit a predisposition to develop IgAN which is based on quantitative and qualitative abnormalities in their systemic IgA immune response. Specifically, they may have an abnormally large serum IgAl response composed of relatively high avidity, antigen-specific antibody and antigen non-specific IgA rheumatoid factor. This response may produce complement fixing immune complexes with relatively large size and low isoelectric point. Such complexes are potentially nephritogenic. To test this hypothesis, the systemic response to an in vivo oral immunization with oral polio vaccine or keyhole limpet hemocyanin will be studied in patients with IgA nephropathy, healthy community controls, healthy siblings or parents, spouses, and patients with other forms of glomerulonephritis. The quantity of antigen specific serum IgA and IgG and antigen non-specific IgARF will be determined post-immunization. The antigen-specific response will be characterized by antibody size, subclass distribution and avidity. The isoelectric point distribution of post-immunization, circulating immune complexes containing C3, IgA and/or IgG will be determined. Antigen-specific IgA production by cultured peripheral blood lymphocytes obtained after in vivo immunization will also be quantitated and characterized. These lymphocytes will be stimulated in vitro with the antigen used in vivo. It is hoped that these studies will define the characteristics of an immune response which predisposes an individual to IgA nephropathy. Recognition of such predisposed individuals would permit prospective studies of disease acquisition and progression and could provide important insights into disease pathogenesis.